CN104470920A - Solid state form of vemurafenib choline salt - Google Patents

Solid state form of vemurafenib choline salt Download PDF

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Publication number
CN104470920A
CN104470920A CN201380035844.3A CN201380035844A CN104470920A CN 104470920 A CN104470920 A CN 104470920A CN 201380035844 A CN201380035844 A CN 201380035844A CN 104470920 A CN104470920 A CN 104470920A
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China
Prior art keywords
wei luofeini
salt
choline salt
solid
preparation
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CN201380035844.3A
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Chinese (zh)
Inventor
F·莱曼
W·阿尔布雷克特
R·古瑟尔
R·塞利格
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Ratiopharm GmbH
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Ratiopharm GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/40—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton

Abstract

The present invention relates to Vemurafenib choline salt, solid state forms thereof, processes for preparation thereof and formulations thereof. The present invention also relates to the use of the solid state forms of Vemurafenib choline salt for preparing Vemurafenib or other Vemurafenib salts, and solid state forms thereof. Vemurafenib has the following chemical structure:

Description

The Wei Luofeini choline salt of solid-state form
The mutual reference of related application
This application claims the U.S. Provisional Application the 61/667th submitted on July 3rd, 2012, the right of priority of No. 769, its full content includes this specification sheets in by way of reference.
Technical field
The present invention relates to Wei Luofeini choline salt and esilate, its solid-state form, its preparation method and preparation thereof.
The invention still further relates to the Wei Luofeini of solid-state form, its preparation method, its preparation, and solid-state form is to the conversion of Wei Luofeini salt.
Background technology
Wei Luofeini, propane-1-sulfonic acid { 3-[5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl]-2,4-difluorophenyl }-acid amides, has the following chemical structure:
Wei Luofeini is BRAF kinase inhibitor, and it is with trade(brand)name commercially available, be used for the treatment of the metastatic melanoma patient that BRAF V600E suddenlys change.Wei Luofeini tablet contains the Wei Luofeini of 240mg, as the coprecipitate of Wei Luofeini and hydroxypropyl methylcellulose acetate succinate (HPMCAS).
US 7,863,288 disclose Wei Luofeini.WO 2010/114928 discloses I type and the II N-type waferN of Wei Luofeini; Its mesylate, tosylate, maleate, oxalate, dichloroacetate, and contain the solid dispersion of Wei Luofeini and ionic polymer, wherein the ratio of Wei Luofeini and ionic polymer is about 1: 9 to about 5: 5, is preferably about 3: 7 (based on weighing scales).WO 2010/129570 discloses the noncrystal complex compound of Wei Luofeini and L-arginine salt and 1B salt.WO 2011/057974 describes the solid dispersion of Wei Luofeini, and describes compared with crystalline form, and the Wei Luofeini of amorphous form has the solubleness of improvement in water, but it is unstable.WO 2012/161776 discloses other solid form and the salt of Wei Luofeini, comprises hydrochloride.
The different salt of active pharmaceutical ingredient and solid-state form (comprising solvation form) may have different characteristics.This species diversity in the characteristic of different salt and solid-state form and solvate can provide basis for improving preparation (such as by contributing to the feature of better processing or process), improving stripping curve or improving stability (polymorphic form and chemical stability) and shelf-life.These changes in the characteristic of different salt and solid-state form also can provide the improvement to final formulation, such as, improve bioavailability if use it for.The different salt of active pharmaceutical ingredient and solid-state form and solvate also can produce various polymorphic form or crystalline form, this can then provide extra chance to utilize change in the characteristic and feature providing the solid active pharmaceutical composition of the product of improvement.
---there is different crystal forms---and be the characteristic of some molecules and molecular complex in heteromorphism.Single compound, as Wei Luofeini, the various multiple polymorphic form with different crystal structure and physical property can be produced, this physical property be such as fusing point, thermal behavior (such as, being measured by thermogravimetric analysis-" TGA " or dsc-" DSC "), powder x-ray diffraction (PXRD) collection of illustrative plates, infrared absorption dactylogram, Raman absorption collection of illustrative plates and solid-state ( 13c-) NMR collection of illustrative plates.One or more these technology can be used to distinguish the different polymorphic forms of compound.
Find that the new salt of medicament production and polymorphic forms and solvate can provide the material of the processing characteristics with expectation, such as be easy to process, be easy to processing, package stability and be easy to purifying, or as contributing to the crystalline intermediates form of the expectation changing into other salt or polymorphic forms.New salt, polymorphic forms and the solvate of the compound of pharmaceutically useful also can provide the chance of the performance characteristic (stripping curve, bioavailability etc.) improving medicament production.It expands the repertoire that formulation science man can be used for the material that preparation is optimized, such as by providing the product with different qualities (such as different crystalline habits, higher crystallinity or polymorphic stability), it can provide better processing or processing feature, the stripping curve of improvement or the shelf-life of improvement.At least due to these reasons, need the other salt of Wei Luofeini and solid-state form (comprising solvation form).
Summary of the invention
The invention provides Wei Luofeini salt, particularly Wei Luofeini esilate and Wei Luofeini choline, and solid-state form; With the method for these compounds of preparation.Wei Luofeini and the Wei Luofeini salt that present invention also offers solid-state form is for the preparation of the purposes of Wei Luofeini or other Wei Luofeini salt and solid-state form thereof.
The invention provides the pharmaceutical composition and preparation and preparation method thereof of at least one (or binding substances) in Wei Luofeini esilate and choline salt, its solid-state form, the Wei Luofeini esilate comprising solid-state form and choline salt.
The present invention also provides Wei Luofeini esilate and choline and solid-state form thereof, and the Wei Luofeini of solid-state form is for the preparation of the purposes of pharmaceutical composition and preparation.The present invention also provides containing Wei Luofeini or the Wei Luofeini esilate of with good grounds solid form of the present invention and any one of choline salt and solid-state form thereof or the pharmaceutical composition of mixture.Described pharmaceutical composition also can comprise the pharmaceutically acceptable vehicle of at least one, produces pharmaceutical preparation thus.
The present invention is also provided for the method for the preparation preparing Wei Luofeini and Wei Luofeini salt, and described method comprises any one of salt of the present invention or solid-state form or mixture and the pharmaceutically acceptable excipient composition of at least one.
The Wei Luofeini of any solid-state form; Wei Luofeini esilate or Wei Luofeini choline and its pharmaceutical composition of solid-state form and Wei Luofeini and preparation can be used as medicine, especially for the medicine of Therapeutic cancer as defined in this article.
The present invention also provides by needing its patient to treat the pharmaceutical composition of upper significant quantity and the method for Therapeutic cancer patient, described pharmaceutical composition comprises at least one in Wei Luofeini, Wei Luofeini esilate of solid-state form of the present invention or Wei Luofeini choline and solid-state form thereof or binding substances, and the optionally pharmaceutically acceptable vehicle of at least one.Present invention also offers by the method needing its patient to give pharmaceutical composition and Therapeutic cancer patient, described pharmaceutical composition comprises Wei Luofeini, Wei Luofeini esilate of solid-state form of the present invention of the upper significant quantity for the treatment of or at least one of Wei Luofeini choline and solid-state form thereof or binding substances, and the optionally pharmaceutically acceptable vehicle of at least one.
Present invention also offers the purposes of Wei Luofeini salt of the present invention and solid-state form thereof, or at least one aforementioned pharmaceutical compositions and preparation are for the manufacture of the purposes of the medicament of Therapeutic cancer.
Accompanying drawing explanation
Fig. 1 illustrates x-ray diffractogram of powder spectrum (" powder X-ray RD " or " PXRD ") of crystal Wei Luofeini T-1 type.
Fig. 2 illustrates the thermogram of the dsc (" DSC ") of crystal Wei Luofeini T-1 type.
Fig. 3 illustrates crystal Wei Luofeini T-1 type 1h-NMR composes.
Fig. 4 illustrates Wei Luofeini esilate 1h-NMR composes.
Fig. 5 illustrates the x-ray diffractogram of powder spectrum of crystal Wei Luofeini esilate E1 type.
Fig. 6 illustrates the thermogram of the dsc (" DSC ") of crystal Wei Luofeini esilate E1 type.
Fig. 7 illustrates Wei Luofeini choline salt 1h-NMR composes.
Fig. 8 illustrates the x-ray diffractogram of powder spectrum of crystal Wei Luofeini choline C1 type.
Fig. 9 illustrates the thermogram of the dsc (" DSC ") of crystal Wei Luofeini choline C1 type.
Figure 10 illustrates that the LC-MS of Wei Luofeini analyzes.
Figure 11 illustrates N-methyl Wei Luofeini's (" compound 2 ") 1h-NMR composes.
Figure 12 illustrates N-methyl Wei Luofeini's (" compound 2 ") 13c-NMR composes.
Figure 13 illustrates infrared (IR) spectrum of N-methyl Wei Luofeini (" compound 2 ").
Figure 14 illustrates the HPLC color atlas of Wei Luofeini.
Figure 15 illustrates the HPLC color atlas of N-methyl Wei Luofeini (" compound 2 ").
Figure 16 illustrates the solid-state of crystal Wei Luofeini choline C1 type 13c-NMR composes.
Embodiment
The present invention relates to Wei Luofeini salt, as esilate and choline salt; The solid-state form of these salt; Its preparation method and containing at least one of these salt or the pharmaceutical composition of binding substances and preparation.The invention still further relates to pharmaceutical composition and the preparation of the Wei Luofeini of solid-state form, its preparation method, at least one containing these solid-state forms or binding substances.The invention still further relates to the conversion to Wei Luofeini or other Wei Luofeini salt of Wei Luofeini salt and solid-state form thereof.
According to WO 2010/114928 and WO 2010/129570, observe Wei Luofeini and have low-down solubleness, this makes it be difficult to prepare and can cause the bioavailability of difference.
Amorphous Wei Luofeini can improve solubleness, but it is unstable.
The base addition salt (as sodium salt and sylvite) that WO 2010/129570 also mentions other is difficult to be separated and moisture absorption.In addition, those salt have been found also containing a large amount of residual solvents.Stable, the solvent-free and sane crystallized form attempting the described salt of exploitation is unsuccessful.Be recorded in Wei Luofeini arginine in WO 2010/129570 and Lysine Complex is considered to noncrystal complex compound.But its PXRD collection of illustrative plates demonstrates crystallinity to a certain degree.
Consistent with the latter, find, under many circumstances, Wei Luofeini free alkali is converted into acid salt or base addition salt is impossible, and the precipitation of free alkali can be caused or produce the noncrystal complex compound of free alkali and respective acid or alkali.Such as, the conversion that can not realize various Wei Luofeini amine salt has been observed.
Among other situations, the invention provides Wei Luofeini choline salt, especially with highly crystalline state, it can be amorphous form.The Wei Luofeini choline of highly crystalline has the solubleness of improvement and has high chemistry and crystallization purity, and this makes it be suitable as pharmacy acceptable salt.Crystal Wei Luofeini choline can be used directly to the preparation preparing high soluble, without the need to the solid dispersion preparation of the activeconstituents containing amorphous form.Described solid dispersion preparation is not too economical and undertakes the potential recrystallization of activeconstituents,---it can have great effect to the solubility property of drug substances and clinical efficacy therefore---also must be controlled to make the quality control more requiring solid dispersion, even if partial recrystallisation.
Salt of the present invention and solid-state form can have and be selected from following at least one advantageous feature: chemical purity, mobility, solubleness, form or crystal habit, stability (such as package stability, dewatering stability and polymorphic inversion stability), agent of low hygroscopicity and low residual solvent levels.
Specifically, salt of the present invention especially can be used as can being purified to provide the intermediate of pure Wei Luofeini.
Crystalline form herein can refer in this article by substantially as figure " described in " graphical data sign.These data comprise such as x-ray diffractogram of powder and solid state NMR spectrum.As in known in the art, graphical data may provide extra technical intelligence to define each solid-state form (so-called " fingerprint ") further, and described solid-state form is not necessarily by describing with reference to independent numerical value or peak position.Under any circumstance, technician can understand described diagrammatic representative data can experience little difference, such as, due to the difference of such as instrument response and the difference of sample concentration and purity factor and cause the difference of peak relative intensity and peak position, this is known by the technical staff.But technician easily can compare graphical data in Ben Wentu from the graphical data that unknown crystal form produces and determine that two groups of graphical datas characterize identical crystalline form or characterize two kinds of different crystalline forms.The crystalline form of the Wei Luofeini salt characterized as figure " described in " graphical data herein therefore by be understood to include with as described in have compared with figure so little difference graphical data any crystalline form of Wei Luofeini salt of characterizing, as known as technical staff.
Crystalline form (or polymorphic form) can refer to essentially no any other crystalline form (or polymorphic form) in this article.Statement used herein in this context " any other form essentially no " will be interpreted as the motif compound meaning described crystalline form and comprise any other form of less than 20%, less than 10%, less than 5%, less than 2% or less than 1%, such as, measured by PXRD.Therefore, be described in this article the polymorphic form of the Wei Luofeini of any other polymorphic Form essentially no or its salt by being understood as containing being greater than 80 % by weight, be greater than 90 % by weight, be greater than 95 % by weight, be greater than 98 % by weight or be greater than 99 % by weight each theme polymorphic forms.Therefore, in some embodiments of the present invention, the polymorphic form of described Wei Luofeini or its salt can comprise one or more other crystalline forms of the described compound of 1 % by weight to 20 % by weight, 5 % by weight to 20 % by weight or 5 % by weight to 10 % by weight.
Used herein, unless stated otherwise, PXRD peak reported here preferably uses CuK αradiation, measure.
Article (such as reaction mixture) can be characterized by this article and be in or be allowed to arrive " room temperature "---usually referred to as " RT ".This temperature meaning described article is close to the temperature or identical with the temperature in space residing for article (such as room or stink cupboard) in space (such as room or stink cupboard) residing for article.
Statement used herein " room temperature " refers to the temperature between about 20 DEG C to about 30 DEG C, or the temperature of about 22 DEG C to about 27 DEG C, or the temperature of about 25 DEG C.Usually, room temperature range is about 20 DEG C to about 25 DEG C.
Method or step can refer to that " spending the night " carries out in this article.This refers to the timed interval of the leap hours of darkness for described method or step, and in that time, described method or step can not be observed on one's own initiative.Term used herein " spends the night " and refers to about 8 little periods up to about 20 hours or about 10 little periods up to about 18 hours.The described period also can refer to 15 little of about 20 hours, be often referred to about 16 little of about 20 hours.
Statement used herein " wet crystalline form " refers to the moist polymorphic form using the technology of any routine to remove residual solvent.The example of such routine techniques can be but be not limited to evaporation, vacuum-drying, oven dry, under nitrogen flowing drying etc.
Statement used herein " dry crystalline form " refers to the polymorphic form using the technology of any routine to remove the drying of residual solvent.The example of such routine techniques can be but be not limited to evaporation, vacuum-drying, oven dry, under nitrogen flowing drying etc.
Unless stated otherwise, the term " anhydrous " relevant to crystal Wei Luofeini or Wei Luofeini salt (such as Wei Luofeini choline C1 type) used herein refer to do not comprise in crystal any with the crystal Wei Luofeini of the crystal water of that define, stoichiometric amount (or other solvents).In addition, " anhydrous " form comprise by TGA or by NMR measure be not more than 2 % by weight water or organic solvent.
Unless stated otherwise, term used herein " solvate " refers to the crystalline form including solvent in crystalline structure in.When described solvent is water, solvate so-called " hydrate ".Solvent in solvate can stoichiometric amount exist, and also can non-stoichiometric amount exist.
The amount of the solvent used in chemical process (such as reaction or crystallization) can refer to multiple " volume (volumes) " or " volume (vol) " or " V " in this article.Such as, a kind of material can refer to be suspended in the solvent of 10 volumes (or 10vol or 10V).In this article, this statement is interpreted as meaning every gram by the solvent milliliter number of suspension material, therefore, the material of 5 grams is suspended in the usage quantity meaning described solvent in the solvent of 10 volumes be every gram by the solvent of suspension material 10 milliliters, or in this example, be 50mL solvent.In another case, term " v/v " can be used to the volume number showing to be added to the solvent in liquid mixture, based on the volumeter of described mixture.Such as, MTBE (1.5v/v) is added to the MTBE meaning to add 150mL in the reaction mixture of 100ml.
The term relevant to crystal Wei Luofeini used herein is nonhygroscopic refers to that the water absorbed by crystal Wei Luofeini is less than 0.2 % by weight, as such as by TGA measure.Water can be such as atmospheric water.
As used herein, the Wei Luofeini salt that relevant to Wei Luofeini or Wei Luofeini salt of the present invention or its solid-state form term " separation " is corresponding to be physically separated from the reaction mixture that it is formed or its solid-state form.
As used herein, term " decompression " refers to the pressure of about 10 millibars to about 50 millibars.
As used herein, and unless otherwise stated, the term " thermodynamic stability " relevant to crystal Wei Luofeini or Wei Luofeini salt refers under certain conditions, such as, heat, melt or dissolve, and crystal is to the resistance (resistance) of polymorphic inversion.In some embodiments, described term refers to that crystal Wei Luofeini or Wei Luofeini salt form are less than 20%, 10%, 5%, 1% or 0.5% (w/w) to the transformation efficiency of Wei Luofeini or the Wei Luofeini salt of any other solid-state form.In some embodiments, described transformation efficiency is 1% to 20%, 1% to 10% or 1% to 5% (w/w).
The present invention also comprises Wei Luofeini tetrahydrofuran (THF) (" THF ") solvate.
The present invention also comprises the Wei Luofeini of crystalline form, is appointed as T-1 type.T-1 shape characterizes by following one or more: 7.6,9.9,13.0,15.9 and 20.5 degree of 2-θ ± 0.2, degree 2-θ place has the Powder XRD pattern at peak; Substantially Powder XRD pattern as shown in Figure 1; With the arbitrary combination of these data.
Or, T-1 type characterizes by Powder XRD pattern, 7.6,9.9,13.0,15.9 and 20.5 degree of 2-θ ± 0.2, a degree 2-θ place has peak to described Powder XRD pattern, and be selected from a degree 2-θ place, 8.4,11.6,18.8,24.8,25.3 and 38.7 degree of 2-θ ± 0.2 also have any one, two, three, four, five or six peaks.
T-1 type also can be characterized by DSC thermogram as shown in Figure 2 substantially.
Above-mentioned T-1 type can be THF solvate.The THF content that described T-1 solvate can have be the Wei Luofeiniyue 0.25 of every 1 molar equivalent to about 0.50 molar equivalent, as 1measured by H-NMR.T-1 type 1h-NMR as shown in Figure 3.
Should be appreciated that T-1 type defines by any may combination of the above-mentioned data listed.
The Wei Luofeini of above-mentioned solid-state form can be used to preparation Wei Luofeini salt and solid-state form thereof.The Wei Luofeini of above-mentioned solid-state form also can be used for pharmaceutical compositions and preparation.
Present invention also offers Wei Luofeini esilate.
Described Wei Luofeini esilate is by substantially as shown in Figure 4 1h-NMR spectrum characterizes.Described Wei Luofeini esilate can be solid, is preferably crystalline solid.
Present invention also offers the Wei Luofeini esilate of crystalline form, be appointed as E1 type.E1 type characterizes by following one or more: 7.0,13.9,17.3,18.5,18.8 and 19.1 degree of 2-θ ± 0.2, degree 2-θ place has the Powder XRD pattern at peak; Substantially Powder XRD pattern as shown in Figure 5; With the arbitrary combination of these data.
Or, E1 type characterizes by Powder XRD pattern, 7.0,13.9,17.3,18.5,18.8 and 19.1 degree of 2-θ ± 0.2, a degree 2-θ place has peak to described Powder XRD pattern, and be selected from a degree 2-θ place, 14.5,21.1,22.4,25.8 and 27.1 degree of 2-θ ± 0.2 also have any one, two, three, four or five peaks.
E1 type also characterizes by DSC thermogram as shown in Figure 6 substantially.
Above-mentioned E1 type can be anhydrous form.
Should be appreciated that T-1 type defines by any possible combination of the above-mentioned data listed.
Present invention also offers Wei Luofeini choline salt.
Described Wei Luofeini choline salt is by substantially as shown in Figure 7 1h-NMR spectrum characterizes.Described Wei Luofeini choline salt can be solid, is preferably crystalline solid.
Present invention also offers the Wei Luofeini choline of crystalline form, be appointed as C1 type.C1 type characterizes by following one or more: 7.9,12.4,13.8,19.2 and 20.6 degree of 2-θ ± 0.2, degree 2-θ place has the Powder XRD pattern at peak; Substantially Powder XRD pattern as shown in Figure 8; The solid-state 13C NMR in 136.3,119.4,116.3,56.2 and 53.6ppm, ± 0.2ppm place with characteristic peak composes; Compose at described characteristic peak with in the solid-state 13C NMR between-13.2 ,-30.1 ,-33.2 ,-93.3 and the peak at-95.9ppm ± 0.1ppm place with chemical shift difference of 149.5ppm ± 0.2ppm respectively; Substantially solid-state 13C NMR as shown in figure 16 composes; With the combination of these data.
Usually, the signal of minimum chemical shift is shown at 13.7 ± 1ppm place in the chemical shift district of 0 to 200ppm.
Or, C1 type characterizes by Powder XRD pattern, 7.9,12.4,13.8,19.2 and 20.6 degree of 2-θ ± 0.2, a degree 2-θ place has peak to described Powder XRD pattern, and be selected from a degree 2-θ place, 13.0,14.1,16.0,16.3 and 16.6 degree of 2-θ ± 0.2 also have any one, two, three, four or five peaks.
C1 type also characterizes by DSC thermogram as shown in Figure 9 substantially.
C1 type can be anhydrous form.
The crystal C1 type of Wei Luofeini choline characterizes by independent each above-mentioned characteristic peak and/or all possible combination, such as by 7.9,12.4,13.8,19.2 and 20.6 degree of 2-θ ± 0.2, degree 2-θ place has X-ray powder diffraction pattern and the X-ray powder diffraction pattern as depicted in figure 8 at peak, or the DSC thermogram at display peak as depicted in figure 9.
Depend on they with which kind of solid-state form any compare, described Wei Luofeini and Wei Luofeini salt and crystalline form can have the advantageous feature being selected from following at least one: the residual solvent of chemistry or polymorphic purity, mobility, solubleness, dissolution rate, bioavailability, form or crystal habit, stability (such as about the chemical stability of polymorphic inversion and thermostability and mechanical stability, package stability, dewatering stability), agent of low hygroscopicity and low levels and favourable processing and treatment characteristic (as compressibility) or tap density.
Specifically, described Wei Luofeini choline salt, particularly crystal C1 type are nonhygroscopic and have high chemical purity.And it shows good water solubility properties, such as, there is compared with Wei Luofeini the water solubility of raising.In addition, it is stable that crystal C1 type stores at least 7 months periods in envrionment conditions (i.e. room temperature and atmospheric moisture), and its at least 2 week under 45 DEG C and 75% relative humidity (RH) is also stable.In addition, Wei Luofeini choline, as crystal C1 type salt, can be used to prepare the oral preparations with relative tabloid or capsule size, i.e. tablet or capsule, the mol ratio of Wei Luofeini and choline is about 1: 1, and it is highly conducive to preparing the pharmaceutical composition with high medicine charge capacity.Increase the alternative of solubleness, the co-precipitation of such as Wei Luofeini and polymkeric substance, can cause polymkeric substance and API more at high proportion, this can increase the size of tablet or capsule.
The above-mentioned salt of Wei Luofeini and solid-state form can be used to preparation Wei Luofeini or other Wei Luofeini salt; Its solid-state form; With its pharmaceutical composition and pharmaceutical preparation.Find, in other cases, it is very useful that the above-mentioned salt of Wei Luofeini and its solid-state form have highly purified Wei Luofeini for preparation.
The invention provides the method for the preparation of Wei Luofeini, such as, by preparation any one salt of the present invention or solid-state form; And alkalization or acidifying described in salt to obtain Wei Luofeini.Described method also can comprise any other salt Wei Luofeini of gained being converted into Wei Luofeini, or is converted into its solid-state form.Described conversion can comprise, such as, by the Wei Luofeini of gained and suitable acid or alkali reaction to obtain corresponding acid salt or base addition salt.Or, described conversion transforms by salt to be carried out, by Wei Luofeini acid salt and the pKa value acid-respons lower than the pKa value of the acid of the first Wei Luofeini acid salt, or by Wei Luofeini base addition salt and the pKa value alkali reaction higher than the pKa value of the alkali of the first Wei Luofeini base addition salt.
Wei Luofeini and the Wei Luofeini salt of above-mentioned solid-state form and solid-state form thereof can be used to pharmaceutical compositions and pharmaceutical preparation.The invention provides the method for the preparation for the preparation of Wei Luofeini and Wei Luofeini salt, described method comprises any one of salt of the present invention and solid-state form or mixture and the pharmaceutically acceptable excipient composition of at least one.The present invention also comprises 1) pharmaceutical composition and preparation, it contains Wei Luofeini, Wei Luofeini salt of solid-state form or any one of its solid-state form or binding substances, as mentioned above, and, when pharmaceutical preparation, the pharmaceutically acceptable vehicle of at least one; 2) Wei Luofeini, Wei Luofeini salt of above-mentioned solid-state form or any one of its solid-state form or binding substances are in the purposes of pharmaceutical compositions; 3) method of Therapeutic cancer; With 4) Wei Luofeini, Wei Luofeini salt of solid-state form as above or the one of their solid-state form or binding substances, as medicament, be used in particular for the medicament of Therapeutic cancer.Described pharmaceutical composition also can be used to prepare medicament.Present invention also offers crystalline form as above, as medicament.
The present invention also describes the fluoro-3-of compound 2,6-bis-[methyl-(propane-1-alkylsulfonyl)-amino]-phenylformic acid, is called compound 1 herein:
Compound 1 can be the impurity that the fluoro-3-of Wei Luofeini intermediate 2,6-bis-(propane-1-sulfuryl amino)-phenylformic acid---is called compound 1a herein---,
And can react further according to building-up process and therefore pollute final Wei Luofeini product.
Invention further describes compound, propane-1-sulfonic acid { 3-[5-(the chloro-phenyl of 4-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl]-2,4-difluorophenyl }-methvl-amid, is called N-methyl Wei Luofeini or compound 2 herein:
The molecular weight of compound 2 is 503 ([M+H] +=m/z 504) (analyzed by LC-MS and measure, as shown in Figure 10).
Compound 2 by suitable analytical procedure as 1h-NMR, 13c-NMR and IR characterizes.
1h NMR (400MHz, acetone-d 6) δ ppm 1.03 (t, J=7.43Hz) 1.84 (m, 2H) 3.20 (m, 2H) 3.32 (s, 3H) 7.23 (m, 1H) 7.40 (m, J=6.26,6.26Hz) 7.55 (d, J=8.60Hz, 2H) 7.72 (m, 1H) 7.79 (d, J=8.60Hz, 2H) 8.16 (s, 1H) 8.70 (d, J=2.35Hz, 1H) 8.76 (s, 1H) 11.88 (s, 1H).Compound 2 1h NMR composes as shown in figure 11.
13c NMR (100MHz, acetone-d 6) δ ppm 12.3,16.9,37.7,52.2,63.3,112.2,112.4,116.7,117.8,127.7,128.0,129.0,129.1,130.4,131.1,132.8,132.9,133.2,137.5,137.7,144.3,149.2,157.1,157.4,159.6,177.2,180.4,204.1.Compound 2 13c NMR composes as shown in figure 12.
IR(ATR)[cm -1]：3095，2981，2840，1617，1592，1474，1416，1332，1255，1162，1138，1097，1014，953，912，862，821，791，652。The IR spectrum of compound 2 as shown in figure 13.
Compound 2 characterizes by any combination of above-mentioned data.
Such as, above-claimed cpd 1 and compound 2 can be used as reference marker and are used as reference standard to analyze the purity of Wei Luofeini and to determine the amount of those impurity in Wei Luofeini sample.In another embodiment, the present invention relates to the analytical procedure of the impurity profile of test or mensuration Wei Luofeini by use above-claimed cpd 1 and/or 2.
Describe the present invention with reference to some preferred embodiment, consider specification sheets, other embodiments can become apparent to those skilled in the art.The following example by referring to the preparation and application specifically describing composition of the present invention sets forth the present invention further.It will be readily apparent to one skilled in the art that not departing from scope of the present invention, many modification relating to materials and methods can be implemented.
its (NMR) spectroscopic method that shakes of nuclear-magnetism:
Instrument: Varian Mercury 400Plus NMR spectrograph, Oxford AS, 400MHz.
Sample dissolution is in DMSO-d6.
powder x-ray diffraction spectrogram (" PXRD ") method:
Sample is in the upper analysis of D8Advance x-ray powder diffraction instrument (Bruker-AXS, Karlsruhe, Germany).By described sample at silicon sample frame higher slice.During measuring, described specimen holder rotates with 20rpm in the plane being parallel to its surface.Other conditions for measuring are summarized as follows.Raw data EVA program (Bruker-AXS, Germany) is analyzed.
dsc (" DSC ") method:
crystal Wei Luofeini T-1 type:
Instrument: Mettler Toledo DSC 822E coupling Mettler ToledoGas-Flow-Controller TS0800GC1 (Mettler-Toledo GmbH, GieBen, Germany)
Aluminium crucible: 40 μ L
Lid: perforation
Temperature range: 30 DEG C to 350 DEG C
Heating rate: 10 DEG C/min
Nitrogen flushing process: 50mL/min
Software: STARe Version.8.10
Explain: endothermal processes
crystal Wei Luofeini esilate E1 type and crystal Wei Luofeini choline C1 type:
Instrument: Varian Mercury 400Plus NMR Spectrometer, Oxford AS, 400MHz
Instrument: Mettler Toledo DSC 822E coupling Mettler ToledoGas-Flow-Controller TS0800GC1 (Mettler-Toledo GmbH, GieBen, Germany)
Aluminium crucible: 40 μ L
Lid: perforation
Temperature range: 30 DEG C to 300 DEG C
Heating rate: 10 DEG C/min
Nitrogen flushing process: 50mL/min
Software: STARe Version.8.10
Explain: endothermal processes
hPLC/UV method:
method A:
Instrument: Agilent 1200
Volume injected: 2 μ L
Solvent orange 2 A: acetonitrile
Solvent B:0.2% formic acid+0.1%HFBA pH.2.21
Flow: 0.7ml/min
Temperature: 40 DEG C
Post: Phenomenex Kinetex C18100A, 150*4.6mm, 2.6 μm
lC-MS method:
Instrument: Agilent 1200 coupling Esquire HCT (Bruker Daltonics)
Chromatographic condition:
Instrument: Agilent 1200
Volume injected: 2 μ L
Solvent orange 2 A: acetonitrile
Solvent B:0.2% formic acid+0.1%HFBA pH.2.21
Flow: 0.7ml/min
Temperature: 40 DEG C
Post: Phenomenex Kinetex C18100A, 150*4.6mm, 2.6 μm of tables 1:
Time [minute] Solvent B [%]
0.00 40
8.00 15
20.00 15
20.00 40
water absorbability method
Vapor sorption test is carried out at the temperature of 25 DEG C with humidity cycle as follows in instrument SPSx-1 μ (Projekt Messtechnik, Ulm, Germany).
Table 2: humidity cycling conditions
water saturation solubleness
The magnetic stirring apparatus being used for parallel projects is at room temperature used to measure the solubleness of Wei Luofeini choline C1 type with 150rpm.By the salt suspension of about 3mg in phosphoric acid buffer pH 6.8 (USP)+1% cetyl trimethylammonium bromide (HTAB).Described sample is stirred 15 seconds, is analyzed through HPLC by the PTFE filter paper filtering of 0.2 μ.The result of water saturation solubleness is as shown in table 3.
Table 3: the water saturation solubleness of Wei Luofeini choline
Embodiment
Initial Wei Luofeini (also referred to as Wei Luofeini free alkali) is such as by US 7,863,288, and prepared by method disclosed in embodiment 3, its full content is included in by way of reference.
embodiment 1: the preparation of crystal Wei Luofeini T-1 type
At room temperature Wei Luofeini free alkali (200mg) is dissolved in the tetrahydrofuran (THF) of 5mL.Distilled water (10ml) is dropwise added while at room temperature stirring (500rpm).The suspension of gained is also at room temperature separately put 22 hours by Keep agitation 2 hours.Gained precipitates by filtering separation and at 40 DEG C and drying under decompression (20 millibars), obtains the Wei Luofeini THF solvate of buff powder.
embodiment 2: the preparation of crystal Wei Luofeini T-1 type
At room temperature Wei Luofeini free alkali (200mg) is dissolved in the tetrahydrofuran (THF) of 5mL.T-butyl methyl ether (10ml) is dropwise added while at room temperature stirring (500rpm).The suspension of gained is also at room temperature separately put 22 hours by Keep agitation 2 hours.Gained precipitates by filtering separation and at 40 DEG C and drying under decompression (20 millibars), obtains the Wei Luofeini THF solvate of buff powder.
embodiment 3: the preparation of crystal Wei Luofeini T-1 type
At room temperature Wei Luofeini free alkali (200mg) is dissolved in the tetrahydrofuran (THF) of 5mL.Normal hexane (10ml) is dropwise added while at room temperature stirring (500rpm).The suspension of gained is also at room temperature separately put 22 hours by Keep agitation 2 hours.Gained precipitates by filtering separation and at 40 DEG C and drying under decompression (20 millibars), obtains the Wei Luofeini THF solvate of buff powder.
embodiment 4: the preparation of crystal Wei Luofeini ethyl sulfonic acid E1 type
At 30 to 35 DEG C, Wei Luofeini free alkali (0.5g) is suspended in the acetone of 10mL.At 30 to 35 DEG C, add ethyl sulfonic acid (0.11g), and mixture was cooled to 0 to 5 DEG C in 30 minutes.Gained precipitation is also washed with acetone (2mL) by filtering separation.Product is under decompression (20 millibars) dry to obtain the Wei Luofeini esilate of the white powder of 0.57g in room temperature.
embodiment 5: the preparation of crystal Wei Luofeini choline C1 type
At 35 DEG C, Wei Luofeini (500mg, 1.0mmol) is suspended in the acetone of 5mL.Add the methanol solution (45%, 270mg, 1.0mmol) of choline hydroxide, gained mixture stirs 5 minutes at 35 DEG C.Afterwards, the settled solution of gained was cooled to 5 DEG C in 30 minutes, and in open bottles room temperature for overnight.Obtain oily residue, and add 2mL ethanol.By mixture supersound process (using ultrasonic energy process) until obtain settled solution.Add two normal hexanes, and by mixture refrigerator and cooled but 9 days.Gained throw out is filtered, and by washing with alcohol, dry to obtain the Wei Luofeini choline of the white solid of 200mg (33%) at room temperature, at a normal.(purity: surveyed by HPLC 98.4%).
embodiment 6: the preparation of crystal Wei Luofeini choline C1 type
In the suspension of the stirring of Wei Luofeini alkali (1.5g, 3.1mmol) and 15mL acetone, (T=30 to 35 DEG C) adds the choline (45% in methyl alcohol) of 0.9ml (3.1mmol).Gained solution is stirred 5 minutes at 35 DEG C, is cooled to 5 DEG C afterwards, and stir 30 minutes at this temperature, allow it to be warming up to room temperature afterwards.In open bottles, stir period of spending the night, solvent evaporates.5mL ethanol is added in oily residue.Mixture is placed in ultra sonic bath until obtain settled solution.After solution stores 3 days in refrigerator, by formed throw out filter, by the washing with alcohol of 2ml, and under RT dry O/N.Isolate the Wei Luofeini choline salt 0.54g (yield: 29.7%) of high purity (HPLC/UV:99.4 area %).
XRPD and dsc analysis confirm the corresponding C1 type of this solid-state form.
embodiment 7: the preparation of crystal Wei Luofeini choline C1 type
In the suspension of the stirring of 1.5g Wei Luofeini alkali and 15mL acetone, (T=30 to 35 DEG C) adds the choline (45% in methyl alcohol) of 0.9ml.Gained solution is stirred 5 minutes at 35 DEG C, is cooled to room temperature afterwards and is divided into three equal parts.All three parts at room temperature stir O/N in open bottles.1.5mL solvent (bottle 1: Virahol, bottle 2: ethyl acetate and bottle 3: t-butyl methyl ether) is added in oily residue.Described bottle, until obtain after clear soln, is stored 6 days, filtering precipitate by process in ultra sonic bath in refrigerator, with 1.5ml with for precipitated phase solvent wash together, and at room temperature dry O/N.
XRPD analyzes the corresponding C1 type of the solid-state form confirming all three samples.
embodiment 8: the preparation of crystal Wei Luofeini choline C1 type
In the suspension of the stirring of 5g Wei Luofeini alkali and 50mL acetone, (T=30 to 35 DEG C) adds the choline (45% in methyl alcohol) of 3.0ml.Gained solution is stirred 5 minutes at 35 DEG C, is cooled to room temperature afterwards.After the solvent evaporates, solid is obtained.Add 15ml Virahol, suspension is placed in ultra sonic bath (suspension is formed without solution), in refrigerator, stores 1 day afterwards.Throw out is filtered, uses 5ml washed with isopropyl alcohol, and at room temperature dry O/N.2.07g (yield: 80.5%).
XRPD and dsc analysis confirm that described solid-state form corresponds to C1 type.
embodiment 9: propane-1-sulfonic acid { 3-[5-(the chloro-phenyl of 4-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl base]-2,4-difluorophenyl } preparation of-methvl-amid (N-methyl Wei Luofeini, " compound 2 ")
Step 1: propane-1-sulfonic acid { 3-[5-(the chloro-phenyl of 4-) 1-(2,6-dichloro-benzoyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl]-2,4-difluorophenyl }-methvl-amid
Propane-1-sulfonic acid { 3-[5-(the chloro-phenyl of 4-)-1-(2; 6-dichloro-benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-3-carbonyl]-2,4-difluorophenyl }-acid amides (0.5g, 0.8mmol) is dissolved in the dimethyl formamide of 1ml.0.1g sodium carbonate is added when stirring at room temperature.Methyl iodide (70 μ l, 0.16g, 1.1mmol) is dropwise added by syringe when room temperature vigorous stirring.Reaction mixture at room temperature stirs and spends the night.Water is added in the suspension of this stirring, and stirs this mixture 1 hour.Be extracted with ethyl acetate reaction mixture twice (2 × 20ml).Use dried over sodium sulfate organic layer.After organic layer drying, at 46 DEG C and decompression under evaporating solvent.Brownish residual crude product without the need to purifying for further synthesis.
Yield: 0.50g (0.74mmol); The theoretical yield of 98%.
Purity: 93.59% (at 254.4nm place) (method A)
LC-MS: retention time: 12.002 minutes; M/z:676.4
The preparation of step 2:N-methyl Wei Luofeini (" compound 2 ")
By propane-1-sulfonic acid { 3-[5-(the chloro-phenyl of 4-)-1-(2; 6-dichloro-benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-3-carbonyl]-2; 4-difluorophenyl }-methvl-amid (0.5g, 0.7mmol) is at room temperature dissolved in the methyl alcohol of DMF and 0.8ml of 1ml.Add the methanol solution of the ammonia of 15%, mixture is under agitation heated to 50 to 55 DEG C and continues 18 hours.At 43 DEG C and concetrated under reduced pressure clear soln.Again the methyl alcohol (20ml) that is added in mixture is evaporated under decompression at 43 DEG C.Gained residue is carried out flash chromatography (silicon-dioxide; Elutriant: ethyl acetate/normal hexane 2/1).Obtain light brown solid product.
Yield: 0.21g, the theoretical yield of (0.42mmol) 156%.
Purity: 96.89% (254.4nm) (method A)
LC-MS: retention time 6.165 minutes; M/z504.3
1h NMR (400MHz, acetone-d 6) δ ppm 1.03 (t, J=7.43Hz) 1.84 (m, 2H) 3.20 (m, 2H) 3.32 (s, 3H) 7.23 (m, 1H) 7.40 (m, J=6.26,6.26Hz) 7.55 (d, J=8.60Hz, 2H) 7.72 (m, 1H) 7.79 (d, J=8.60Hz, 2H) 8.16 (s, 1H) 8.70 (d, J=2.35Hz, 1H) 8.76 (s, 1H) 11.88 (s, 1H).Compound 2 1h NMR composes as shown in figure 11.
13c NMR (100MHz, acetone-d 6) δ ppm 12.3,16.9,37.7,52.2,63.3,112.2,112.4,116.7,117.8,127.7,128.0,129.0,129.1,130.4,131.1,132.8,132.9,133.2,137.5,137.7,144.3,149.2,157.1,157.4,159.6,177.2,180.4,204.1.Compound 2 13c NMR composes as shown in figure 12.
IR(ATR)[cm -1]：3095，2981，2840，1617，1592，1474，1416，1332，1255，1162，1138，1097，1014，953，912，862，821，791，652。The IR spectrum of compound 2 as shown in figure 13.

Claims (18)

1. Wei Luofeini choline salt.
2. the Wei Luofeini choline salt of claim 1, the mol ratio wherein between Wei Luofeini and choline is about 1: 1.
3. the Wei Luofeini choline salt of claim 1 or 2, it is solid-state form.
4. the Wei Luofeini choline salt any one of aforementioned claims 1 to 3, it is crystallized form.
5. the crystallized form of the Wei Luofeini choline salt of claim 4, is appointed as C1 type, and it characterizes by following one or more: 7.9,12.4,13.8,19.2 and 20.6 degree of 2-θ ± 0.2, degree 2-θ place has the Powder XRD pattern at peak; Powder XRD pattern as shown in Figure 8; Compose at described characteristic peak with in the solid-state 13C NMR between-13.2 ,-30.1 ,-33.2 ,-93.3 and the peak at-95.9ppm ± 0.1ppm place with chemical shift difference of 149.5ppm ± 0.2ppm respectively; Substantially solid-state 13C NMR as shown in figure 16 composes; With the combination of these data.
6. the crystallized form of claim 5, also by being selected from any one of degree 2-θ place, 13.0,14.1,16.0,16.3 and 16.6 degree of 2-θ ± 0.2, the other powder X-ray RD peak of two, three, four or five characterizes.
7. the crystallized form any one of aforementioned claim 5 to 6, is characterized by DSC thermogram as shown in Figure 9 substantially.
8. the crystallized form any one of aforementioned claim 5 to 7, wherein said crystallized form is anhydrous form.
9. pharmaceutical composition, it contains the Wei Luofeini choline salt any one of aforementioned claim 1 to 8.
10. pharmaceutical preparation, it contains Wei Luofeini choline salt any one of aforementioned claim 1 to 8 and the pharmaceutically acceptable vehicle of at least one.
The purposes of Wei Luofeini choline salt in pharmaceutical compositions or preparation any one of 11. aforementioned claims 1 to 8.
12. for the preparation of the method for the pharmaceutical preparation of claim 10, and it comprises the pharmaceutical composition of the Wei Luofeini choline salt any one of claim 1 to 8 or claim 9 and the pharmaceutically acceptable excipient composition of at least one.
Wei Luofeini choline salt any one of 13. claims 1 to 8, the pharmaceutical composition of claim 9 or the pharmaceutical preparation of claim 10, as medicament.
Wei Luofeini choline salt any one of 14. claims 1 to 8, the pharmaceutical composition of claim 9 or the pharmaceutical preparation of claim 10, be used in treatment and suffer from the experimenter of cancer.
15. treatments suffer from the method for oncological patients, comprise the Wei Luofeini choline salt any one of claim 1 to 8, the pharmaceutical composition of claim 9 or the pharmaceutical preparation of claim 10 for the treatment of significant quantity.
Wei Luofeini choline salt any one of 16. claims 1 to 8 is for the preparation of Wei Luofeini, other Wei Luofeini salt; Its solid-state form; With the purposes of its pharmaceutical preparation.
17. for the preparation of the method for Wei Luofeini, comprises the Wei Luofeini choline salt of preparation any one of claim 1 to 8 and is translated into Wei Luofeini.
The method of 18. claims 17, wherein said conversion is completed to obtain the method for Wei Luofeini by the Wei Luofeini choline salt comprised any one of acidifying claim 1 to 8.
CN201380035844.3A 2012-07-03 2013-07-02 Solid state form of vemurafenib choline salt Pending CN104470920A (en)

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